BEAM: An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects

• Sponsor: Chiesi Farmaceutici S.p.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03084718
• Collaborator: (none)
• Enrollment: 610
• Locations: 134
• Arms: 5
• Actual Duration (Months): 16.3
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the dose-response of different doses of CHF 781 Pressurized Metered Dose Inhaler (pMDI) on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target patient population.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: CHF 718 pMDI; Drug: Placebo pMDI; Drug: Beclomethasone Dipropionate (BDP)	Phase 2

Detailed Description

This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose ranging 5-arm parallel group study to identify the optimal dose of CHF 781 pMDI with respect to lung function and other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol as needed and background inhaled corticosteroid (ICS), patients will be randomized to one of the 5 study treatment groups. After randomization, patients will be assessed after 4 and 8 weeks of study treatment at the center. A follow-up phone call will be performed a week after the last visit.

During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication will be recorded via subject diary. Treatment-Emergent Adverse Events (TEAEs) will be assessed and recorded throughout the study. At screening and subsequent visits, patients will undergo physical and vital signs examinations, spirometry measurements, and 12-lead ECG. Routine hematology, blood chemistry, and pregnancy testing will be performed before enrollment and at end of study. 24-hr urine cortisol and creatinine will be assessed before and after the first dose and just before the last dose of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 610 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: An 8-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 3 Doses of CHF 718 pMDI (HFA Beclomethasone Dipropionate Via Pressured Metered Dose Inhaler) in Asthmatic Subjects.
• Actual Study Start Date: Jul 28, 2017
• Actual Primary Completion Date: Nov 28, 2018
• Actual Study Completion Date: Dec 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	Drug: CHF 718 pMDI; Dose Response: Test one of three different doses of CHF 718 pMDI
Experimental: Treatment B CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	Drug: CHF 718 pMDI; Dose Response: Test one of three different doses of CHF 718 pMDI
Experimental: Treatment C CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Drug: CHF 718 pMDI; Dose Response: Test one of three different doses of CHF 718 pMDI
Placebo Comparator: Treatment D Placebo Control, Placebo; CHF 718 pMDI matched Placebo: 4 inhalations BID;	Drug: Placebo pMDI; Placebo Control
Active Comparator: Treatment E Beclomethasone dipropionate (BDP) Hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID;	Drug: Beclomethasone Dipropionate (BDP); Active Control; Other Names: QVAR® 80µg

Outcome Measures

Primary Outcome Measures

1. Pre-dose Morning FEV1 at Week 8 - Change From Baseline [Baseline, Week 8]

   Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) at Week 8. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;

Secondary Outcome Measures

1. Pre-dose Morning FEV1 at Week 4 - Change From Baseline [Baseline, Week 4]

   Change from baseline in pre-dose morning FEV1 at Week 4. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;

2. Pre-dose Morning FVC at Week 4 and 8 - Change From Baseline [Baseline, Week 4, Week 8]

   Change from baseline in pre-dose morning FVC at Week 4 and 8. Spirometry, used to measure FVC, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FVC were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FVC=Forced vital capacity;

3. Asthma Control Questionnaire-7© (ACQ-7) Score at Week 4 and Week 8 - Change From Baseline [Baseline, Week 4, Week 8]

   The ACQ consists of 7 items: 6 simple self-administered questions referring to asthma control and rescue treatment usage with 1 week recall, and a 7th item consisting of the percent (%) predicted FEV1 completed by clinic staff. Scoring uses a 7-point scale: 0 = "totally controlled" and 6 = "severely uncontrolled". The ACQ score was calculated as the average of all 7 items. Definitions: ACQ-7 score=Asthma Control Questionnaire-7©; Information regarding the American Thoracic Society ACQ questionnaire is also available at: https://member.thoracic.org/members/assemblies/assemblies/srn/questionaires/acq.php; Baseline ACQ-7 score = ACQ score recorded at V2 (Week 0) Day 1, before randomization; FEV1=Forced expiratory volume in the 1st second;

4. Average Use of Rescue Medication - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Change from baseline in average use of rescue medication, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. Definitions: Baseline=For the efficacy variable -- average use of rescue medication -- derived from the electronic diary (eDiary), baseline values were the averages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

5. Percentage (%) of Rescue Medication-free Days - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Change from baseline in percentage (%) of rescue medication-free days. An increased value indicates improvement from baseline. Definitions: Baseline=For the efficacy variable -- percentage (%) of rescue medication-free days -- derived from the electronic diary (eDiary), baseline values were the averages/percentages recorded during the run-in period. Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

6. Overall Daily Asthma Symptoms Scores - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Overall daily asthma symptoms scores - Change From Baseline (am and pm). Subjects had to record asthma symptom score (overall symptoms, cough, wheeze, chest tightness and breathlessness) in the am (night-time asthma symptom score) and in the pm (daytime asthma symptom score). These data were collected in the subject's diary. Daily asthma symptoms score were performed separately for am score and pm score and also as a total, where the total equals the sum of the am and pm scores. Degree of asthma symptoms by score: 0=None, 1=Mild, 2=Moderate, and 3=Severe. Baseline=Averages values during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

7. Percentage (%) of Asthma Symptoms-free Days - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Change from baseline in Percentage (%) of asthma symptoms-free days. Asthma symptoms-free days is the number of days with a total asthma score=0 (daily morning plus evening asthma score). Subjects recorded asthma symptom score as described in the Outcome measure #7. Definitions: Baseline=For the efficacy variables -- daytime and night-time asthma symptom scores -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

8. Percentage (%) of Asthma Control Days - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Change from baseline in percentage (%) of asthma control days, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. This outcome measure was calculated according to the following definition: Days with a total daily morning + evening asthma score = 0 AND No rescue medication use. Definitions: Baseline=For the efficacy variable -- asthma control days -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

9. Pre-dose Peak Expiratory Flow (PEF) (L/Min) (Morning and Evening) - Change From Baseline [Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)]

   Change from baseline in pre-dose Peak Expiratory Flow (PEF) (Liters/min), morning and evening measurements. Definitions: Baseline=For the efficacy variable -- morning and evening PEF -- derived from the eDiary, the baseline values were the averages/percentages recorded during the run-in period; PEF=evening peak expiratory flow; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening

10. Vital Signs (Systolic and Diastolic Blood Pressure) - Change From Baseline [Baseline, Week 4, Week 8]

    Vital signs (systolic and diastolic blood pressure) at baseline, week 4, and week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; DBP=Diastolic blood pressure; SBP=Systolic blood pressure;

11. 12-lead ECG Parameters - Heart Rate - Change From Baseline [Baseline, Week 8]

    12-lead electrocardiogram (12-lead ECG) parameter - heart rate (HR) was measured at baseline (Day 1) and Week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; bpm=Beats per minute;

12. 12-lead ECG Parameters - PR, QRS, QTcF - Change From Baseline. [Baseline, Week 8]

    12-lead electrocardiogram (12-lead ECG) parameters - PR, QRS, QTcF intervals - were measured at baseline (Day 1) and Week 8. Changes from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0); QTcF=Fridericia-corrected QT interval; msec=Millisecond;

13. 12-lead ECG Parameters - Prolonged QTcF - Change From Baseline [Baseline, Week 8]

    Number of participants with prolonged QTcF. Change from baseline. Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; QTcF=Fridericia-corrected QT interval;

14. 24-hr Urine Free Cortisol - Change From Baseline [Baseline, Week 8]

    24-hr Urinary Free Cortisol - Change From Baseline. For the evaluation of the 24-hr Urine-Free cortisol excretion, 24-hour urine samples were collected. Urine-free cortisol was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;

15. 24-hr Creatinine - Change From Baseline. [Baseline, Week 8]

    24-hr Creatinine - Change From Baseline. For the evaluation of the 24-hr creatinine excretion, 24-hour urine sample were collected. Creatinine was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects aged ≥18 and ≤75 years who have signed an Informed Consent form prior to initiation of any study-related procedure.

• A diagnosis of asthma as defined in the Global Initiative for Asthma (GINA) Report, 2016, documented for at least 1 year prior to screening.

• Subjects with poorly controlled or uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire 7 © (ACQ-7) ≥1.5 (this criterion must be met at screening and at randomization visits).

• Subjects with a pre-bronchodilator Forced Expiratory Volume in the 1st Second (FEV1) ≥50% and <85% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits.

• Subjects with a positive response to a reversibility test at screening (pre - post BD), within 1 year prior to or at screening defined as ΔFEV1≥12% and ≥200 mL over baseline within 30 minutes after inhaling 4 puffs of albuterol HFA 90µg/actuation.

• Use of inhaled corticosteroids (low/medium dose according to GINA Report 2016) with or without a long-acting bronchodilator (LABD) for 3 months (stable dose in the last 4 weeks) before screening visit (V).

• A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter, and pMDI inhalers.

• A basal morning (7-10 am) serum cortisol level between 7-28 µg/dL at screening visit (V1).

• A Body Mass Index (BMI): 18.5 ≤ BMI <35 kg/m^2.

Exclusion Criteria:

• Pregnant (as evident by a positive urine human chorionic gonadotropin (hCG) or serum β-hCG test) or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to use a highly effective birth control method

• Subjects who suffer from chronic obstructive pulmonary disease (COPD) as defined by the GOLD Report 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as defined in GINA Report, 2016.

• Inability to carry out pulmonary lung function testing, to comply with study procedures or with study drug intake.

• Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking history of >10 pack-years or having stopped smoking one year or less prior to screening visit.

• History of life-threatening asthma, clinically significant uncontrolled disease or respiratory infection.

• An asthma exacerbation requiring oral corticosteroids within 3 months or hospitalization within 6 months prior to screening.

• Subjects with unresolved bacterial or viral respiratory tract, sinus or middle ear infection affecting asthma status within 2 weeks prior to screening.

• Subjects who received a vaccination within 2 weeks prior to screening or during the run-in.

• Subjects with oral candidiasis at screening or at randomization.

• Subjects with any clinically significant, uncontrolled condition

• Subjects who have clinically significant cardiovascular condition

• Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement.

• Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening and randomization visits.

• Subjects with known intolerance/hypersensitivity or contra-indication to treatment with ß2-adrenergic receptor agonists, inhaled corticosteroids or propellant gases/excipients.

• Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-Immunoglobulin E (IgE), anti-Interleukin 5 (IL5), or other monoclonal or polyclonal antibodies within 12 weeks prior to screening.

• Use of potent cytochrome P450 3A4 inhibitors and inducers within 4 weeks prior to screening.

• History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening.

• Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.

• Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order.

• Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chiesi Investigational Site	Birmingham	Alabama	United States	35244
2	Chiesi Investigational Site	Montgomery	Alabama	United States	36106
3	Chiesi Investigational Site	Phoenix	Arizona	United States	85014
4	Chiesi Investigational Site	Surprise	Arizona	United States	85374
5	Chiesi Investigational Site	Tempe	Arizona	United States	85283
6	Chiesi Investigational Site	Little Rock	Arkansas	United States	72209
7	Chiesi Investigational Site	Anaheim	California	United States	92801
8	Chiesi Investigational Site	Encinitas	California	United States	92024
9	Chiesi Investigational Site	Escondido	California	United States	92025
10	Chiesi Investigational Site	Fullerton	California	United States	92835
11	Chiesi Investigational Site	Huntington Beach	California	United States	92647
12	Chiesi Investigational Site	Long Beach	California	United States	90806
13	Chiesi Investigational Site	Los Angeles	California	United States	90017
14	Chiesi Investigational Site	Los Angeles	California	United States	90025
15	Chiesi Investigational Site	Los Angeles	California	United States	90048
16	Chiesi Investigational Site	Newport Beach	California	United States	92663
17	Chiesi Investigational Site	North Hollywood	California	United States	91606
18	Chiesi Investigational Site	Rolling Hills Estates	California	United States	90274
19	Chiesi Investigational Site	Sacramento	California	United States	95821
20	Chiesi Investigational Site	San Diego	California	United States	92120
21	Chiesi Investigational Site	San Diego	California	United States	92123
22	Chiesi Investigational Site	San Jose	California	United States	95117
23	Chiesi Investigational Site	Tustin	California	United States	92780
24	Chiesi Investigational Site	Westminster	California	United States	92683
25	Chiesi Investigational Site	Boulder	Colorado	United States	80301
26	Chiesi Investigational Site	Colorado Springs	Colorado	United States	80907
27	Chiesi Investigational Site	Denver	Colorado	United States	80230
28	Chiesi Investigational Site	Greenwood	Colorado	United States	80112
29	Chiesi Investigational Site	Wheat Ridge	Colorado	United States	80033
30	Chiesi Investigational Site	Aventura	Florida	United States	33180
31	Chiesi Investigational Site	Clearwater	Florida	United States	33765
32	Chiesi Investigational Site	Daytona Beach	Florida	United States	32117
33	Chiesi Investigational Site	Doral	Florida	United States	33166
34	Chiesi Investigational Site	Gainesville	Florida	United States	32607
35	Chiesi Investigational Site	Hialeah	Florida	United States	33016
36	Chiesi Investigational Site	Kissimmee	Florida	United States	34741
37	Chiesi Investigational Site	Lauderdale Lakes	Florida	United States	33319
38	Chiesi Investigational Site	Loxahatchee Groves	Florida	United States	33470
39	Chiesi Investigational Site	Maitland	Florida	United States	32751
40	Chiesi Investigational Site	Miami	Florida	United States	33133
41	Chiesi Investigational Site	Miami	Florida	United States	33144
42	Chiesi Investigational Site	Miami	Florida	United States	33157
43	Chiesi Investigational Site	Miami	Florida	United States	33165
44	Chiesi Investigational Site	Miami	Florida	United States	33173
45	Chiesi Investigational Site	Orlando	Florida	United States	32801
46	Chiesi Investigational Site	Palmetto Bay	Florida	United States	33157
47	Chiesi Investigational Site	Plantation	Florida	United States	33322
48	Chiesi Investigational Site	Pompano Beach	Florida	United States	33060
49	Chiesi Investigational Site	Saint Cloud	Florida	United States	34769
50	Chiesi Investigational Site	Sarasota	Florida	United States	34239
51	Chiesi Investigational Site	Winter Park	Florida	United States	32789
52	Chiesi Investigational Site	Dacula	Georgia	United States	30019
53	Chiesi Investigational Site	Duluth	Georgia	United States	30096
54	Chiesi Investigational Site	Gainesville	Georgia	United States	30501
55	Chiesi Investigational Site	Marietta	Georgia	United States	30060
56	Chiesi Investigational Site	Savannah	Georgia	United States	31405
57	Chiesi Investigational Site	Chicago	Illinois	United States	60607
58	Chiesi Investigational Site	Chicago	Illinois	United States	60612
59	Chiesi Investigational Site	Crowley	Louisiana	United States	70526
60	Chiesi Investigational Site	New Orleans	Louisiana	United States	70124
61	Chiesi Investigational Site	Baltimore	Maryland	United States	21236
62	Chiesi Investigational Site	Bethesda	Maryland	United States	20814
63	Chiesi Investigational Site	Fall River	Massachusetts	United States	02720
64	Chiesi Investigational Site	Fall River	Massachusetts	United States	02721
65	Chiesi Investigational Site	North Dartmouth	Massachusetts	United States	02747
66	Chiesi Investigational Site	South Dartmouth	Massachusetts	United States	02747
67	Chiesi Investigational Site	Detroit	Michigan	United States	48202
68	Chiesi Investigational Site	Minneapolis	Minnesota	United States	55402
69	Chiesi Investigational Site	Columbia	Missouri	United States	65203
70	Chiesi Investigational Site	Festus	Missouri	United States	63028
71	Chiesi Investigational Site	Rolla	Missouri	United States	65401
72	Chiesi Investigational Site	Saint Louis	Missouri	United States	63110
73	Chiesi Investigational Site	Saint Louis	Missouri	United States	63141
74	Chiesi Investigational Site	Warrensburg	Missouri	United States	64093
75	Chiesi Investigational Site	Missoula	Montana	United States	59808
76	Chiesi Investigational Site	Omaha	Nebraska	United States	68114
77	Chiesi Investigational Site	Las Vegas	Nevada	United States	89102
78	Chiesi Investigational Site	Las Vegas	Nevada	United States	89146
79	Chiesi Investigational Site	Skillman	New Jersey	United States	08558
80	Chiesi Investigational Site	Albuquerque	New Mexico	United States	87108
81	Chiesi Investigational Site	Albuquerque	New Mexico	United States	87109
82	Chiesi Investigational Site	Bronx	New York	United States	10455
83	Chiesi Investigational Site	Brooklyn	New York	United States	11201
84	Chiesi Investigational Site	New York	New York	United States	10016
85	Chiesi Investigational Site	New York	New York	United States	10022
86	Chiesi Investigational Site	Charlotte	North Carolina	United States	28207
87	Chiesi Investigational Site	Charlotte	North Carolina	United States	28277
88	Chiesi Investigational Site	Gastonia	North Carolina	United States	28054
89	Chiesi Investigational Site	Hendersonville	North Carolina	United States	28739
90	Chiesi Investigational Site	Hickory	North Carolina	United States	28601
91	Chiesi Investigational Site	Monroe	North Carolina	United States	28112
92	Chiesi Investigational Site	Mooresville	North Carolina	United States	28117
93	Chiesi Investigational Site	Winston-Salem	North Carolina	United States	27103
94	Chiesi Investigational Site	Cincinnati	Ohio	United States	45231
95	Chiesi Investigational Site	Cincinnati	Ohio	United States	45242
96	Chiesi Investigational Site	Dayton	Ohio	United States	45409
97	Chiesi Investigational Site	Dayton	Ohio	United States	45417
98	Chiesi Investigational Site	Grove City	Ohio	United States	43123
99	Chiesi Investigational Site	Munroe Falls	Ohio	United States	44262
100	Chiesi Investigational Site	Toledo	Ohio	United States	43617
101	Chiesi Investigational Site	Edmond	Oklahoma	United States	73034
102	Chiesi Investigational Site	Medford	Oregon	United States	97504
103	Chiesi Investigational Site	Portland	Oregon	United States	97202
104	Chiesi Investigational Site	East Providence	Rhode Island	United States	02914
105	Chiesi Investigational Site	East Providence	Rhode Island	United States	02941
106	Chiesi Investigational Site	Warwick	Rhode Island	United States	02886
107	Chiesi Investigational Site	Anderson	South Carolina	United States	29621
108	Chiesi Investigational Site	Gaffney	South Carolina	United States	29340
109	Chiesi Investigational Site	Greenville	South Carolina	United States	29615
110	Chiesi Investigational Site	Rock Hill	South Carolina	United States	29732
111	Chiesi Investigational Site	Spartanburg	South Carolina	United States	29301
112	Chiesi Investigational Site	Spartanburg	South Carolina	United States	29303
113	Chiesi Investigational Site	Union	South Carolina	United States	29379
114	Chiesi Investigational Site	Chattanooga	Tennessee	United States	37419
115	Chiesi Investigational Site	Chattanooga	Tennessee	United States	37421
116	Chiesi Investigational Site	Knoxville	Tennessee	United States	37909
117	Chiesi Investigational Site	Smyrna	Tennessee	United States	37167
118	Chiesi Investigational Site	Spring Hill	Tennessee	United States	37174
119	Chiesi Investigational Site	Allen	Texas	United States	75013
120	Chiesi Investigational Site	Beaumont	Texas	United States	77702
121	Chiesi Investigational Site	Cypress	Texas	United States	77429
122	Chiesi Investigational Site	Dallas	Texas	United States	75224
123	Chiesi Investigational Site	Dallas	Texas	United States	75231
124	Chiesi Investigational Site	El Paso	Texas	United States	79903
125	Chiesi Investigational Site	McKinney	Texas	United States	75069
126	Chiesi Investigational Site	Pearland	Texas	United States	77584
127	Chiesi Investigational Site	Plano	Texas	United States	75093
128	Chiesi Investigational Site	San Antonio	Texas	United States	78217
129	Chiesi Investigational Site	Sherman	Texas	United States	75092
130	Chiesi Investigational Site	Saint George	Utah	United States	84790
131	Chiesi Investigational Site	South Burlington	Vermont	United States	05403
132	Chiesi Investigational Site	Norfolk	Virginia	United States	23507
133	Chiesi Investigational Site	Everett	Washington	United States	98208
134	Chiesi Investigational Site	Greenfield	Wisconsin	United States	53228

Sponsors and Collaborators

• Chiesi Farmaceutici S.p.A.

Investigators

• Principal Investigator: David Bernstein, MD, Bernstein Clinical Research Center, LLC

Study Documents (Full-Text)

• Study Protocol - Jun 5, 2018
• Statistical Analysis Plan - Jan 30, 2019

More Information

Additional Information:

• From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017.
• COPD Foundation - What is COPD
• Global Initiative For Asthma - GINA Report 2016
• Centers for Disease Control and Prevention - Most Recent Asthma Data
• Chiesi Farmaceutici S.p.A. - Respiratory
• Chiesi Farmaceutici S.p.A - Press Release: Chiesi Farmaceutifici is the first company to submit a marketing authorisation application to the European Medicine Agency for a triple combination for the treatment of COPD
• Wikipedia entry - Beclomethasone dipropionate
• WebMD LLC - Serum Cortisol
• Mayo Clinic - Test ID: COCOU; Cortisol/Cortisone, Free, 24 Hour, Urine
• Quest Diagnostics- Cortisol, Free and Cortisone, 24 Hour Urine with Creatinine

Publications

• Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel N, FitzGerald M; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007 Apr 17;146(8):545-55. Epub 2007 Feb 19.
• Anderson WJ, Lipworth BJ. Does body mass index influence responsiveness to inhaled corticosteroids in persistent asthma? Ann Allergy Asthma Immunol. 2012 Apr;108(4):237-42. doi: 10.1016/j.anai.2011.12.006. Epub 2012 Jan 21.
• Andréjak C, Nielsen R, Thomsen VØ, Duhaut P, Sørensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013 Mar;68(3):256-62. doi: 10.1136/thoraxjnl-2012-201772. Epub 2012 Jul 10.
• Arievich H, Overend T, Renard D, Gibbs M, Alagappan V, Looby M, Banerji D. A novel model-based approach for dose determination of glycopyrronium bromide in COPD. BMC Pulm Med. 2012 Dec 8;12:74. doi: 10.1186/1471-2466-12-74.
• Aubier M, Wettenger R, Gans SJ. Efficacy of HFA-beclomethasone dipropionate extra-fine aerosol (800 microg day(-1)) versus HFA-fluticasone propionate (1000 microg day(-1)) in patients with asthma. Respir Med. 2001 Mar;95(3):212-20.
• Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. 2007 Nov;101(11):2240-7. Epub 2007 Aug 8.
• Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, Vanden Burgt J, Donnell D, Hannon S, Colice GL. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol. 1999 Dec;104(6):1215-22.
• Callejas SL, Biddlecombe RA, Jones AE, Joyce KB, Pereira AI, Pleasance S. Determination of the glucocorticoid fluticasone propionate in plasma by automated solid-phase extraction and liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 1998 Nov 6;718(2):243-50.
• Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005 Mar;127(3):809-17.
• Chiesi Farmaceutici S.p.A. A double blind double dummy, multiple dose comparison of two parallel groups comparing a daily dose of extrafine BDP HFA 400µg vs. BDP CFC 1000µg in asthmatic patients over an 8-week treatment period. 2005 Jul;DM/PR/3303/006/03.
• Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009 Sep;34(3):641-7. doi: 10.1183/09031936.00193908. Epub 2009 May 14.
• Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Lettis S, Calverley PM. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015 Jan;12(1):27-34. doi: 10.1513/AnnalsATS.201409-413OC.
• Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R, Higgins M, Kramer B; INVOLVE (INdacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety) Study Investigators. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010 Jun;65(6):473-9. doi: 10.1136/thx.2009.125435.
• Edwards D, Berry JJ. The efficiency of simulation-based multiple comparisons. Biometrics. 1987 Dec;43(4):913-28.
• Ellepola AN, Samaranayake LP. Inhalational and topical steroids, and oral candidosis: a mini review. Oral Dis. 2001 Jul;7(4):211-6. Review.
• Ferguson GT, Calverley PMA, Anderson JA, Jenkins CR, Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Chest. 2009 Dec;136(6):1456-1465. doi: 10.1378/chest.08-3016. Epub 2009 Jul 6.
• Frith PA, Thompson PJ, Ratnavadivel R, Chang CL, Bremner P, Day P, Frenzel C, Kurstjens N; Glisten Study Group. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax. 2015 Jun;70(6):519-27. doi: 10.1136/thoraxjnl-2014-206670. Epub 2015 Apr 3.
• GlaxoSmithKline. ARNUITY® ELLIPTA® US Prescribing Information. Research Triangle Park, North Carolina; 2014 Aug.
• GlaxoSmithKline. BREO® ELLIPTA® US Prescribing Information. Research Triangle Park, North Carolina; 2015 Apr.
• GlaxoSmithKline. Cross Discipline Team Leader Review: Application number 204275Orig1s000; 2013 Apr 1.
• Gross G, Thompson PJ, Chervinsky P, Vanden Burgt J. Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma. Chest. 1999 Feb;115(2):343-51.
• Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med. 2012 Jan;106(1):91-101. doi: 10.1016/j.rmed.2011.09.002. Epub 2011 Oct 29.
• Hankinson JL, Bang KM. Acceptability and reproducibility criteria of the American Thoracic Society as observed in a sample of the general population. Am Rev Respir Dis. 1991 Mar;143(3):516-21.
• Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of American Thoracic Society-recommended spirometry reference values in a multiethnic sample of adults: the multi-ethnic study of atherosclerosis (MESA) lung study. Chest. 2010 Jan;137(1):138-45. doi: 10.1378/chest.09-0919. Epub 2009 Sep 9.
• Johnell O, Pauwels R, Löfdahl CG, Laitinen LA, Postma DS, Pride NB, Ohlsson SV. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler. Eur Respir J. 2002 Jun;19(6):1058-63.
• Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med. 2006 Apr;100(4):616-21. Epub 2005 Oct 13.
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• Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. Int J Chron Obstruct Pulmon Dis. 2008;3(1):127-36.
• Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 Oct 15;(10):CD010177. doi: 10.1002/14651858.CD010177.pub2. Review.
• Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014 Mar 10;(3):CD010115. doi: 10.1002/14651858.CD010115.pub2. Review.
• Leuchs AK, Zinserling J, Brandt A, Wirtz D, Benda N. Choosing Appropriate Estimands in Clinical Trials. Ther Innov Regul Sci. 2015 Jul;49(4):584-592. doi: 10.1177/2168479014567317.
• Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011 Aug;66(8):699-708. doi: 10.1136/thx.2011.160028. Epub 2011 May 20. Review.
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• Mallinckrodt C, Roger J, Chuang-stein C, Molenberghs G, Lane PW, O'Kelly M, et al. Missing data: turning guidance into action. Stat Biopharm Res. 2013;5(4):369-82.
• Mallinckrodt CH, Kenward MG. Conceptual Considerations regarding Endpoints, Hypotheses, and Analyses for Incomplete Longitudinal Clinical Trial Data. Drug Inf J. 2009; 43(4): 449-58.
• Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest. 2002 May;121(5 Suppl):121S-126S. Review.
• Matthys H, Nowak D, Hader S, Kunkel G. Efficacy of chlorofluorocarbon-free beclomethasone dipropionate 400 micrograms day-1 delivered as an extrafine aerosol in adults with moderate asthma. Respir Med. 1998 Jun;92 Suppl A:17-22.
• McGarvey L, Niewoehner D, Magder S, Sachs P, Tetzlaff K, Hamilton A, Korducki L, Bothner U, Vogelmeier C, Koch A, Ferguson GT. One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis. COPD. 2015;12(5):484-93. doi: 10.3109/15412555.2014.991864. Epub 2015 Feb 18.
• Miller DP, Watkins SE, Sampson T, Davis KJ. Long-term use of fluticasone propionate/salmeterol fixed-dose combination and incidence of cataracts and glaucoma among chronic obstructive pulmonary disease patients in the UK General Practice Research Database. Int J Chron Obstruct Pulmon Dis. 2011;6:467-76. doi: 10.2147/COPD.S14247. Epub 2011 Sep 16.
• Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 Aug;26(2):319-38.
• National Research Council (US) Panel on Handling Missing Data in Clinical Trials. The Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): National Academies Press (US); 2010.
• Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014 Feb 26;311(8):806-14. doi: 10.1001/jama.2014.732.
• Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016 Sep;4(9):731-741. doi: 10.1016/S2213-2600(16)30148-5. Epub 2016 Jul 23.
• Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW, Wedzicha JA, Barnes NC. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax. 2016 Feb;71(2):118-25. doi: 10.1136/thoraxjnl-2015-207021. Epub 2015 Nov 19.
• Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005 Nov;26(5):948-68.
• Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Craig T, Denlinger L, Engle LL, DiMango EA, Fahy JV, Israel E, Jarjour N, Kazani SD, Kraft M, Lazarus SC, Lemanske RF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Wasserman SI, Walter MJ, Wechsler ME, Chinchilli VM, Bleecker ER; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28;363(18):1715-26. doi: 10.1056/NEJMoa1008770. Epub 2010 Sep 19.
• Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5-40. Review.
• Rachelefsky GS, Liao Y, Faruqi R. Impact of inhaled corticosteroid-induced oropharyngeal adverse events: results from a meta-analysis. Ann Allergy Asthma Immunol. 2007 Mar;98(3):225-38.
• Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy ML, O'Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan SD, Szefler SJ, Thomas MD, Wenzel SE; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009 Jul 1;180(1):59-99. doi: 10.1164/rccm.200801-060ST.
• Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004 Jul;126(1):213-9. Review.
• Siler TM, Kerwin E, Singletary K, Brooks J, Church A. Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies. COPD. 2016;13(1):1-10. doi: 10.3109/15412555.2015.1034256. Epub 2015 Oct 9.
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• Responsible Party: Chiesi Farmaceutici S.p.A.
• ClinicalTrials.gov Identifier: NCT03084718
• Other Study ID Numbers: CCD-05993AA3-01
• First Posted: Mar 21, 2017
• Last Update Posted: Dec 14, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Asthma; Beclomethasone

Study Results

Participant Flow

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^® 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID); TDD of BDP: 100 μg;	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID; TDD of BDP: 400 μg;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID; TDD of BDP: 800 μg;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate Hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate Hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Period Title: Overall Study
STARTED	120	120	122	124	124
COMPLETED	109	110	110	110	120
NOT COMPLETED	11	10	12	14	4

Baseline Characteristics

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D	Treatment E	Total
Arm/Group Description	CHF 718 pMDI 100 µg TDD	CHF 718 pMDI 400 µg TDD	CHF 718 pMDI 800 µg TDD	Placebo Control	Beclomethasone dipropionate Hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate Hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID, Total Daily Dose (TDD) of BDP: 320 μg;	Total of all reporting groups
Overall Participants	118	116	120	124	124	602
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	2 1.6%	0 0%	2 0.3%
Between 18 and 65 years	97 82.2%	101 87.1%	107 89.2%	110 88.7%	105 84.7%	520 86.4%
>=65 years	21 17.8%	15 12.9%	13 10.8%	12 9.7%	19 15.3%	80 13.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.2 (13.58)	48.1 (14.38)	48.2 (13.83)	45.4 (16.17)	48.8 (14.24)	48.1 (14.52)
Sex: Female, Male (Count of Participants)
Female	74 62.7%	77 66.4%	76 63.3%	72 58.1%	77 62.1%	376 62.5%
Male	44 37.3%	39 33.6%	44 36.7%	52 41.9%	47 37.9%	226 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	34 28.8%	34 29.3%	30 25%	40 32.3%	28 22.6%	166 27.6%
Not Hispanic or Latino	84 71.2%	82 70.7%	90 75%	84 67.7%	96 77.4%	436 72.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%	0 0%	1 0.8%	1 0.8%	0 0%	3 0.5%
Asian	1 0.8%	1 0.9%	0 0%	0 0%	2 1.6%	4 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.9%	0 0%	0 0%	0 0%	1 0.2%
Black or African American	27 22.9%	23 19.8%	28 23.3%	21 16.9%	24 19.4%	123 20.4%
White	78 66.1%	82 70.7%	84 70%	93 75%	93 75%	430 71.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	11 9.3%	9 7.8%	7 5.8%	9 7.3%	5 4%	41 6.8%
Region of Enrollment (participants) [Number]
United States	118 100%	116 100%	120 100%	124 100%	124 100%	602 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	83.2 (14.9)	77.9 (15.6)	79.5 (14.5)	80.5 (15.5)	78.8 (14.7)	80.0 (15.1)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.6 (9.5)	168.2 (9.2)	167.8 (8.4)	170.0 (9.8)	167.9 (9.7)	168.7 (9.4)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.9 (4.0)	27.4 (4.3)	28.2 (4.3)	27.8 (4.6)	27.9 (4.0)	28.0 (4.3)
Time since first diagnosis of asthma (months) [Median (Full Range) ]
Median (Full Range) [months]	372.3	372.8	373.9	306.6	385.0	363.8
Age at first diagnosis of asthma (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.4 (18.3)	17.3 (18.1)	17.2 (17.7)	17.4 (18.0)	16.5 (15.8)	17.2 (17.6)
Asthma medication category at study entry (Count of Participants)
Short-Acting β2-agonist (SABA), (albuterol)	115 97.5%	115 99.1%	117 97.5%	124 100%	121 97.6%	592 98.3%
Leukotriene Receptor Antagonist (LTRA)	24 20.3%	7 6%	17 14.2%	18 14.5%	17 13.7%	83 13.8%
Theophylline	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Inhaled Corticosteroid (ICS) alone	23 19.5%	26 22.4%	34 28.3%	36 29%	28 22.6%	147 24.4%
ICS/ Long-Acting β2-agonist (LABA), (free or fixed combination)	93 78.8%	88 75.9%	86 71.7%	88 71%	94 75.8%	449 74.6%
ICS/Long-Acting Muscarinic Antagonist (LAMA), (free combination)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
ICS/LABA/LAMA	2 1.7%	2 1.7%	0 0%	0 0%	1 0.8%	5 0.8%
Short-Acting Muscarinic Antagonist (SAMA)	0 0%	0 0%	0 0%	0 0%	1 0.8%	1 0.2%
SAMA/SABA	0 0%	0 0%	1 0.8%	0 0%	0 0%	1 0.2%
ICS dose before study (Count of Participants)
Low daily dose	50 42.4%	50 43.1%	48 40%	54 43.5%	51 41.1%	253 42%
Medium daily dose	68 57.6%	66 56.9%	72 60%	70 56.5%	73 58.9%	349 58%
Smoking habits (Count of Participants)
Ex-smoker	13 11%	18 15.5%	18 15%	21 16.9%	23 18.5%	93 15.4%
Non-smoker	105 89%	98 84.5%	102 85%	103 83.1%	101 81.5%	509 84.6%
Duration of smoking (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.3 (8.2)	9.5 (6.1)	13.7 (9.1)	10.4 (8.6)	10.3 (6.7)	10.8 (7.7)
Number of pack-years (pack-years) [Median (Full Range) ]
Median (Full Range) [pack-years]	2.0	2.7	4.0	3.5	3.0	3.0
FEV1 at baseline (litres) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [litres]	2.131 (0.500)	2.128 (0.545)	2.114 (0.531)	2.268 (0.603)	2.130 (0.571)	2.155 (0.553)
FEV1 (% predicted normal value) at baseline (percent of predicted normal value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent of predicted normal value]	68.5 (8.4)	68.3 (7.8)	68.4 (8.7)	68.6 (8.0)	68.8 (8.9)	68.5 (8.4)
FVC at baseline (litres) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [litres]	3.159 (0.971)	3.164 (0.931)	3.101 (0.855)	3.415 (1.020)	3.197 (0.851)	3.209 (0.931)
FEV1/FVC at baseline (ratio of the parameters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio of the parameters]	0.696 (0.104)	0.687 (0.099)	0.693 (0.098)	0.677 (0.104)	0.675 (0.106)	0.685 (0.102)

Outcome Measures

1. Primary Outcome

Title	Pre-dose Morning FEV1 at Week 8 - Change From Baseline
Description	Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) at Week 8. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation 2 times a day (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations BID;	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID;
Measure Participants	117	115	119	123	124
Least Squares Mean (95% Confidence Interval) [Litres]	0.021	0.090	0.070	-0.023	0.078

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; -0.052 to 0.140
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.113
	Confidence Interval	(2-Sided) 95%; 0.018 to 0.209
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.093
	Confidence Interval	(2-Sided) 95%; -0.003 to 0.188
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.049
	Confidence Interval	(2-Sided) 95%; -0.031 to 0.129
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.612
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.021
	Confidence Interval	(2-Sided) 95%; -0.101 to 0.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.102
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.180
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Pre-dose Morning FEV1 at Week 4 - Change From Baseline
Description	Change from baseline in pre-dose morning FEV1 at Week 4. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;
Time Frame	Baseline, Week 4

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	117	115	119	123	124
Least Squares Mean (95% Confidence Interval) [Litres]	0.021	0.120	0.073	0.003	0.077

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.647
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.060 to 0.097
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.118
	Confidence Interval	(2-Sided) 95%; 0.039 to 0.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.071
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.149
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.099
	Confidence Interval	(2-Sided) 95%; 0.020 to 0.179
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.192
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.131
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.244
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.047
	Confidence Interval	(2-Sided) 95%; -0.126 to 0.032
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.074
	Confidence Interval	(2-Sided) 95%; -0.003 to 0.151
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Pre-dose Morning FVC at Week 4 and 8 - Change From Baseline
Description	Change from baseline in pre-dose morning FVC at Week 4 and 8. Spirometry, used to measure FVC, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FVC were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FVC=Forced vital capacity;
Time Frame	Baseline, Week 4, Week 8

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	117	115	119	123	124
Week 4	0.036	0.099	0.066	0.023	0.056
Week 8	0.014	0.089	0.036	-0.016	0.063

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.780
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.012
	Confidence Interval	(2-Sided) 95%; -0.074 to 0.098
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.162
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.324
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.043 to 0.129
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.153
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; -0.024 to 0.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.482
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.031
	Confidence Interval	(2-Sided) 95%; -0.055 to 0.117
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.463
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.032
	Confidence Interval	(2-Sided) 95%; -0.119 to 0.054
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.453
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	(2-Sided) 95%; -0.052 to 0.117
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.533
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.030
	Confidence Interval	(2-Sided) 95%; -0.064 to 0.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.105
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.199
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; -0.041 to 0.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.169
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.638
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.022
	Confidence Interval	(2-Sided) 95%; -0.071 to 0.116
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.052
	Confidence Interval	(2-Sided) 95%; -0.147 to 0.042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.171
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Asthma Control Questionnaire-7© (ACQ-7) Score at Week 4 and Week 8 - Change From Baseline
Description	The ACQ consists of 7 items: 6 simple self-administered questions referring to asthma control and rescue treatment usage with 1 week recall, and a 7th item consisting of the percent (%) predicted FEV1 completed by clinic staff. Scoring uses a 7-point scale: 0 = "totally controlled" and 6 = "severely uncontrolled". The ACQ score was calculated as the average of all 7 items. Definitions: ACQ-7 score=Asthma Control Questionnaire-7©; Information regarding the American Thoracic Society ACQ questionnaire is also available at: https://member.thoracic.org/members/assemblies/assemblies/srn/questionaires/acq.php; Baseline ACQ-7 score = ACQ score recorded at V2 (Week 0) Day 1, before randomization; FEV1=Forced expiratory volume in the 1st second;
Time Frame	Baseline, Week 4, Week 8

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	117	115	119	123	124
Week 4	-0.43	-0.53	-0.49	-0.27	-0.47
Week 8	-0.53	-0.58	-0.66	-0.43	-0.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.176
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.423
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.574
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Week 4 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.566
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.336
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Week 8 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Average Use of Rescue Medication - Change From Baseline
Description	Change from baseline in average use of rescue medication, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. Definitions: Baseline=For the efficacy variable -- average use of rescue medication -- derived from the electronic diary (eDiary), baseline values were the averages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	118	115	118	124	124
Inter-visit period 1	-0.11	-0.27	-0.14	0.07	-0.13
Inter-visit period 2	-0.12	-0.35	-0.25	0.01	-0.18
Entire treatment period	-0.11	-0.31	-0.20	0.04	-0.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.130
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.811
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.202
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.39 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.60 to -0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.50 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.258
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.423
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.111
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.444
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.285
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage (%) of Rescue Medication-free Days - Change From Baseline
Description	Change from baseline in percentage (%) of rescue medication-free days. An increased value indicates improvement from baseline. Definitions: Baseline=For the efficacy variable -- percentage (%) of rescue medication-free days -- derived from the electronic diary (eDiary), baseline values were the averages/percentages recorded during the run-in period. Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	118	115	118	124	124
Inter-visit period 1	5.9	9.0	6.1	1.5	7.7
Inter-visit period 2	8.9	13.1	10.0	4.1	11.2
Entire treatment period	7.4	11.1	8.1	2.8	9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -1.1 to 10.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.6
	Confidence Interval	(2-Sided) 95%; 2.0 to 13.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; -0.9 to 10.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.275
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -2.5 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.943
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -5.4 to 5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -8.6 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 95%; 0.8 to 11.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.129
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.8
	Confidence Interval	(2-Sided) 95%; -1.4 to 11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.0
	Confidence Interval	(2-Sided) 95%; 2.8 to 15.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.061
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.9
	Confidence Interval	(2-Sided) 95%; -0.3 to 12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -2.0 to 10.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.721
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -5.1 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.328
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -9.4 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.1
	Confidence Interval	(2-Sided) 95%; 1.0 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.101
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; -0.9 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.3
	Confidence Interval	(2-Sided) 95%; 2.8 to 13.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.061
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; -0.2 to 10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.196
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.7
	Confidence Interval	(2-Sided) 95%; -1.9 to 9.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.814
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -4.9 to 6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.291
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -8.6 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 1.3 to 12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Overall Daily Asthma Symptoms Scores - Change From Baseline
Description	Overall daily asthma symptoms scores - Change From Baseline (am and pm). Subjects had to record asthma symptom score (overall symptoms, cough, wheeze, chest tightness and breathlessness) in the am (night-time asthma symptom score) and in the pm (daytime asthma symptom score). These data were collected in the subject's diary. Daily asthma symptoms score were performed separately for am score and pm score and also as a total, where the total equals the sum of the am and pm scores. Degree of asthma symptoms by score: 0=None, 1=Mild, 2=Moderate, and 3=Severe. Baseline=Averages values during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	118	115	118	124	124
Inter-visit period 1	-0.1	-0.1	-0.1	0.0	-0.1
Inter-visit period 2	-0.1	-0.1	-0.1	-0.0	-0.1
Entire treatment period	-0.1	-0.1	-0.1	0.0	-0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.913
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.871
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.958
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.996
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.632
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.630
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.960
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.725
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.764
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage (%) of Asthma Symptoms-free Days - Change From Baseline
Description	Change from baseline in Percentage (%) of asthma symptoms-free days. Asthma symptoms-free days is the number of days with a total asthma score=0 (daily morning plus evening asthma score). Subjects recorded asthma symptom score as described in the Outcome measure #7. Definitions: Baseline=For the efficacy variables -- daytime and night-time asthma symptom scores -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	118	115	118	124	124
Inter-visit period 1	8.6	10.5	10.1	5.7	12.8
Inter-visit period 2	16.4	17.0	17.2	11.7	21.2
Entire treatment period	12.5	13.8	13.6	8.7	17.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.316
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; -2.8 to 8.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.9
	Confidence Interval	(2-Sided) 95%; -0.9 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.128
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -1.3 to 10.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.511
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -3.9 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.610
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -4.3 to 7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.882
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -6.3 to 5.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95%; 1.5 to 12.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.219
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; -2.8 to 12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.166
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; -2.2 to 12.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.151
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.5
	Confidence Interval	(2-Sided) 95%; -2.0 to 12.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.871
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -6.9 to 8.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.837
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -6.8 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.966
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -7.4 to 7.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.5
	Confidence Interval	(2-Sided) 95%; 2.1 to 16.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; -2.5 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.113
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -1.2 to 11.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.120
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; -1.3 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; -5.1 to 7.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.722
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -5.2 to 7.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.966
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -6.5 to 6.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.3
	Confidence Interval	(2-Sided) 95%; 2.2 to 14.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage (%) of Asthma Control Days - Change From Baseline
Description	Change from baseline in percentage (%) of asthma control days, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. This outcome measure was calculated according to the following definition: Days with a total daily morning + evening asthma score = 0 AND No rescue medication use. Definitions: Baseline=For the efficacy variable -- asthma control days -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	118	115	118	124	124
Inter-visit period 1	7.3	10.6	10.4	5.0	12.8
Inter-visit period 2	14.3	16.3	17.5	10.5	20.63
Entire treatment period	10.8	13.4	13.9	7.7	16.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -3.4 to 7.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.6
	Confidence Interval	(2-Sided) 95%; -0.1 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.4
	Confidence Interval	(2-Sided) 95%; -0.2 to 11.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.263
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -2.5 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -2.6 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.965
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -5.9 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.8
	Confidence Interval	(2-Sided) 95%; 2.2 to 13.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; -3.5 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; -1.6 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.063
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 14.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.602
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -5.5 to 9.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.402
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -4.3 to 10.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.753
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -6.3 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.2
	Confidence Interval	(2-Sided) 95%; 2.9 to 17.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.331
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -3.1 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.7
	Confidence Interval	(2-Sided) 95%; -0.5 to 11.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.2
	Confidence Interval	(2-Sided) 95%; 0.1 to 12.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.410
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; -3.6 to 8.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.320
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -3.1 to 9.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.867
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -5.7 to 6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.0
	Confidence Interval	(2-Sided) 95%; 2.9 to 15.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Pre-dose Peak Expiratory Flow (PEF) (L/Min) (Morning and Evening) - Change From Baseline
Description	Change from baseline in pre-dose Peak Expiratory Flow (PEF) (Liters/min), morning and evening measurements. Definitions: Baseline=For the efficacy variable -- morning and evening PEF -- derived from the eDiary, the baseline values were the averages/percentages recorded during the run-in period; PEF=evening peak expiratory flow; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening
Time Frame	Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Outcome Measure Data

Analysis Population Description

Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	116	114	115	121	119
Inter-visit period 1	-2	-3	-4	-6	0
Inter-visit period 2	-4	3	-5	-4	2
Entire treatment period	-3	0.3	-4	-4.9	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.260
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4
	Confidence Interval	(2-Sided) 95%; -3.2 to 11.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.387
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3
	Confidence Interval	(2-Sided) 95%; -4.2 to 10.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.574
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; -5.4 to 9.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.799
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -8.6 to 6.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.577
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2
	Confidence Interval	(2-Sided) 95%; -9.8 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 1 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.764
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -8.8 to 6.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 1 Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -1.1 to 13.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.908
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -9.9 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7
	Confidence Interval	(2-Sided) 95%; -2.2 to 16.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.786
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -10.7 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8
	Confidence Interval	(2-Sided) 95%; -1.7 to 17.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.876
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -10.1 to 8.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8
	Confidence Interval	(2-Sided) 95%; -17.9 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Inter-visit period 2 Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.202
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -3.2 to 15.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment A (CHF 718 pMDI 100 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; -5.9 to 9.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.191
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5
	Confidence Interval	(2-Sided) 95%; -2.6 to 13.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Treatment C (CHF 718 pMDI 800 µg TDD), Treatment D (Placebo)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.914
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -7.4 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment B (CHF 718 pMDI 400 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment B (CHF 718 pMDI 400 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.407
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3
	Confidence Interval	(2-Sided) 95%; -4.6 to 11.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Treatment A (CHF 718 pMDI 100 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment A (CHF 718 pMDI 100 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -9.4 to 6.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Treatment B (CHF 718 pMDI 400 µg TDD), Treatment C (CHF 718 pMDI 800 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment C (CHF 718 pMDI 800 µg TDD) vs Treatment B (CHF 718 pMDI 400 µg TDD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5
	Confidence Interval	(2-Sided) 95%; -12.7 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Treatment D (Placebo), Treatment E (QVAR^®, 320 µg TDD)
	Comments	Entire treatment period Comparison treatment groups were: Treatment E (QVAR^®, 320 µg TDD) vs Treatment D (Placebo)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.118
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -1.6 to 13.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Vital Signs (Systolic and Diastolic Blood Pressure) - Change From Baseline
Description	Vital signs (systolic and diastolic blood pressure) at baseline, week 4, and week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; DBP=Diastolic blood pressure; SBP=Systolic blood pressure;
Time Frame	Baseline, Week 4, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	117	115	119	124	124
SBP, Week 4	-0.4	1.0	0.5	0.6	0.0
SBP, Week 8	1.0	2.5	0.8	0.2	-0.9
DBP, Week 4	-0.1	0.2	-0.8	0.1	0.8
DBP, Week 8	0.8	1.0	0.3	-0.5	1.2

12. Secondary Outcome

Title	12-lead ECG Parameters - Heart Rate - Change From Baseline
Description	12-lead electrocardiogram (12-lead ECG) parameter - heart rate (HR) was measured at baseline (Day 1) and Week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; bpm=Beats per minute;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	116	115	116	121	122
Mean (Full Range) [bpm]	0.6	0.2	0.4	1.2	-0.4

13. Secondary Outcome

Title	12-lead ECG Parameters - PR, QRS, QTcF - Change From Baseline.
Description	12-lead electrocardiogram (12-lead ECG) parameters - PR, QRS, QTcF intervals - were measured at baseline (Day 1) and Week 8. Changes from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0); QTcF=Fridericia-corrected QT interval; msec=Millisecond;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	119	120	121	124	124
PR	-2.6	1.5	-1.9	-1.3	1.0
QRS	0.1	-1.3	0.9	-0.5	-0.3
QTcF	1.6	0.7	0.7	4.6	1.2

14. Secondary Outcome

Title	12-lead ECG Parameters - Prolonged QTcF - Change From Baseline
Description	Number of participants with prolonged QTcF. Change from baseline. Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; QTcF=Fridericia-corrected QT interval;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	119	120	121	124	124
QTcF > 30 msec	6 5.1%	4 3.4%	4 3.3%	9 7.3%	3 2.4%
QTcF > 60 msec	1 0.8%	1 0.9%	0 0%	2 1.6%	1 0.8%

15. Secondary Outcome

Title	24-hr Urine Free Cortisol - Change From Baseline
Description	24-hr Urinary Free Cortisol - Change From Baseline. For the evaluation of the 24-hr Urine-Free cortisol excretion, 24-hour urine samples were collected. Urine-free cortisol was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	99	108	99	103	111
Median (Full Range) [nmol/day]	-3.60	-5.35	-4.10	1.40	-3.50

16. Secondary Outcome

Title	24-hr Creatinine - Change From Baseline.
Description	24-hr Creatinine - Change From Baseline. For the evaluation of the 24-hr creatinine excretion, 24-hour urine sample were collected. Creatinine was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received at least one dose of study treatment.

Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)	Treatment B (CHF 718 pMDI 400 µg TDD)	Treatment C (CHF 718 pMDI 800 µg TDD)	Treatment D (Placebo)	Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);	CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;	CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;	Placebo Control. CHF 718 pMDI matched Placebo: 4 inhalations 2 times a day (BID);	Beclomethasone dipropionate hydrofluoroalkane (HFA) (QVAR^®), Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR^® 80 μg/actuation: 2 inhalations BID;
Measure Participants	101	110	104	107	111
Median (Full Range) [umol/mol]	0.00	0.00	0.00	0.00	0.00

Adverse Events

Time Frame	From the first intake of study medication (visit 2, Week 0) until study completion (Visit 4, week 8) or discontinuation from the study.
Adverse Event Reporting Description	The safety population was used for the evaluation of adverse event (AEs). Safety population=All randomized patients who received at least one dose of study treatment. The overall number of randomized participants in the study=610 (Participant Flow). Nevertheless, the Safety population=608 patients; 2 patients (1 in Group A and 1 in Group C) were excluded because they were mistakenly randomized; they failed to meet inclusion criterion #4 and were withdrawn prior to study drug administration.
Arm/Group Title	Treatment A (CHF 718 pMDI 100 µg TDD)		Treatment B (CHF 718 pMDI 400 µg TDD)		Treatment C (CHF 718 pMDI 800 µg TDD)		Treatment D (Placebo)		Treatment E (QVAR^®, 320 µg TDD)
Arm/Group Description	CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID);		CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID;		CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID;		Placebo Control, Placebo; CHF 718 pMDI matched Placebo: 4 inhalations BID;		QVAR^®, : Active Control Beclomethasone dipropionate hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID;
All Cause Mortality
	Treatment A (CHF 718 pMDI 100 µg TDD)		Treatment B (CHF 718 pMDI 400 µg TDD)		Treatment C (CHF 718 pMDI 800 µg TDD)		Treatment D (Placebo)		Treatment E (QVAR^®, 320 µg TDD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/119 (0%)		1/120 (0.8%)		0/121 (0%)		0/124 (0%)		0/124 (0%)
Serious Adverse Events
	Treatment A (CHF 718 pMDI 100 µg TDD)		Treatment B (CHF 718 pMDI 400 µg TDD)		Treatment C (CHF 718 pMDI 800 µg TDD)		Treatment D (Placebo)		Treatment E (QVAR^®, 320 µg TDD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/119 (0.8%)		2/120 (1.7%)		2/121 (1.7%)		1/124 (0.8%)		0/124 (0%)
Eye disorders
Diplopia	0/119 (0%)	0	1/120 (0.8%)	1	0/121 (0%)	0	0/124 (0%)	0	0/124 (0%)	0
Retinal detachment	0/119 (0%)	0	0/120 (0%)	0	0/121 (0%)	0	1/124 (0.8%)	1	0/124 (0%)	0
General disorders
Chest pain	0/119 (0%)	0	1/120 (0.8%)	1	0/121 (0%)	0	0/124 (0%)	0	0/124 (0%)	0
Infections and infestations
Diverticulitis	0/119 (0%)	0	1/120 (0.8%)	1	0/121 (0%)	0	0/124 (0%)	0	0/124 (0%)	0
Furuncle	0/119 (0%)	0	0/120 (0%)	0	1/121 (0.8%)	1	0/124 (0%)	0	0/124 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	0/119 (0%)	0	1/120 (0.8%)	1	0/121 (0%)	0	0/124 (0%)	0	0/124 (0%)	0
Lower limb fracture	1/119 (0.8%)	1	0/120 (0%)	0	0/121 (0%)	0	0/124 (0%)	0	0/124 (0%)	0
Multiple injuries	0/119 (0%)	0	0/120 (0%)	0	1/121 (0.8%)	1	0/124 (0%)	0	0/124 (0%)	0
Psychiatric disorders
Anxiety	0/119 (0%)	0	0/120 (0%)	0	1/121 (0.8%)	1	0/124 (0%)	0	0/124 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment A (CHF 718 pMDI 100 µg TDD)		Treatment B (CHF 718 pMDI 400 µg TDD)		Treatment C (CHF 718 pMDI 800 µg TDD)		Treatment D (Placebo)		Treatment E (QVAR^®, 320 µg TDD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/119 (15.1%)		8/120 (6.7%)		25/121 (20.7%)		28/124 (22.6%)		21/124 (16.9%)
Infections and infestations
Oral candidiasis	1/119 (0.8%)	1	0/120 (0%)	0	6/121 (5%)	6	0/124 (0%)	0	4/124 (3.2%)	4
Upper respiratory tract infection	6/119 (5%)	6	2/120 (1.7%)	2	3/121 (2.5%)	3	3/124 (2.4%)	3	7/124 (5.6%)	7
Viral upper respiratory tract infection	6/119 (5%)	6	1/120 (0.8%)	1	7/121 (5.8%)	7	6/124 (4.8%)	6	3/124 (2.4%)	3
Respiratory, thoracic and mediastinal disorders
Asthma	4/119 (3.4%)	4	3/120 (2.5%)	3	5/121 (4.1%)	5	11/124 (8.9%)	11	5/124 (4%)	5
Cough	0/119 (0%)	0	2/120 (1.7%)	2	2/121 (1.7%)	2	4/124 (3.2%)	4	1/124 (0.8%)	1
Dyspnoea	1/119 (0.8%)	1	0/120 (0%)	0	2/121 (1.7%)	2	4/124 (3.2%)	4	1/124 (0.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Chiesi can publish and/or present any results of this study at scientific meetings, and to submit the clinical trial data to national and international Regulatory Authorities. Chiesi reserves the right to use such data for industrial purposes. Investigators will inform Chiesi before using the results of the study for publication or presentation, and agree to provide the Sponsor with a copy of the proposed presentation. Data from individual study sites must not be published separately.